The present invention generally features devices and methods for therapeutically treating the inner ear. More particularly, the invention involves a specialized, minimally-invasive technique for transporting therapeutic agents (e.g. drugs and other pharmaceutical compositions) into the inner ear from the middle ear in a highly effective manner.
In order to treat ear disorders, it may often be necessary to deliver therapeutic agents to various ear tissues in a controlled, safe, and efficient manner. For example, a variety of structures have been developed which are capable of delivering/administering therapeutic agents into the external auditory canal of the outer ear. U.S. Pat. No. 4,034,759 to Haerr discloses a hollow, cylindrical tube manufactured of sponge material (e.g. dehydrated cellulose) which is inserted into the external auditory canal of a patient. When liquid medicines are placed in contact with the tube, it correspondingly expands against the walls of the auditory canal. As a result, accidental removal of the tube is prevented. Furthermore, medicine materials absorbed by the tube are maintained in contact with the walls of the external auditory canal for treatment purposes. Other absorbent devices designed for treatment of the external auditory canal and related tissue structures are disclosed in U.S. Pat. No. 3,528,419 to Joechle, U.S. Pat. No. 4,159,719 to Haerr, and U.S. Pat. No. 2,642,065 to Negri. The Negri patent specifically describes a medicine delivery device with an intemally-mounted, frangible medicine container which, when broken, releases liquid medicines into an absorbent member.
However, the delivery of therapeutic agents in a controlled and effective manner is considerably more difficult with respect to tissue structures of the inner ear (e.g. those portions of the ear surrounded by the otic capsule bone and contained within the temporal bone which is the most dense bone tissue in the entire human body). The same situation exists in connection with tissue materials which lead into the inner ear (e.g. the round window membrane). Exemplary inner ear tissue structures of primary importance for treatment purposes include but are not limited to the cochlea, the endolymphatic sac/duct, the vestibular labyrinth, and all of the compartments (and connecting tubes) which include these components. Access to these and other inner ear tissue regions is typically achieved through a variety of structures, including but not limited to the round window membrane, the oval window/stapes footplate, the annular ligament, and the otic capsule/temporal bone, all of which shall be considered xe2x80x9cmiddle-inner ear interface tissue structuresxe2x80x9d as described in greater detail below. Furthermore, as indicated herein, the middle ear shall be defined as the physiological air-containing tissue zone behind the tympanic membrane (e.g. the ear drum) and ahead of the inner ear.
The inner ear tissues listed above are of minimal size and only readily accessible through invasive microsurgical procedures. In order to treat various diseases and conditions associated with inner ear tissues, the delivery of medicines to such structures is often of primary importance. Representative medicines which are typically used to treat inner ear tissues include but are not limited to urea, mannitol, sorbitol, glycerol, lidocaine, xylocaine, epinephrine, immunoglobulins, sodium chloride, steroids, heparin, hyaluronidase, aminoglycoside antibiotics (streptomycin/gentamycin), antioxidants, neurotrophins, nerve growth factors, various therapeutic peptides, and polysaccharides. Of particular interest in this list are compounds which are used to alter the permeability of the round window membrane within the ear using, for example, hyaluronidase and iontophoretic techniques (defined below). Likewise, the treatment of inner ear tissues and/or fluid cavities may involve altering the pressure, volume, electrical activity, and temperature characteristics thereof. Specifically, a precise balance must be maintained with respect to the pressure of various fluids within the inner ear and its associated compartments. Imbalances in the pressure and volume levels of such fluids can cause various problems, including but not limited to conditions known as endolymphatic hydrops, endolymphatic hypertension, perilymphatic hypertension, perilymphatic hydrops, perilymphatic fistula, intracochlear fistula, Meniere""s disease, tinnitus, vertigo, hearing loss related to hair cell or ganglion cell damage/malfunction, and ruptures in various membrane structures within the ear.
Conventional methods for delivery of therapeutic agents to the inner ear involve filling the middle ear with a solution or other carrier of the therapeutic agent (see, e.g., Shea Otolaryngol Clin North Am. 30(6):1051-9 (1997)). Other methods use naturally-occurring materials such as gelatin (e.g., Gelfoam, see, e.g., Silverstein Ann Otol Rhinol Laryngol Suppl. 112:44-8. (1984); Lundman et al. Otolaryngol 112:524 (1992); Nedzelski et al. Am. J. Otol. 14:278-82 (1993); Silverstein et al. Ear Nose Throat J 75:468-88 (1996); Ramsay et al. Otolaryngol. 116:39 (1996); Ruan et al. Hear Res 114:169 (1997); Wanamaker et al. Am. J. Otology 19:170 (1998); Arriaga et al. Laryngoscope 108:1682-5 (1998); and Husmann et al. Hear Res 125:109 (1998)), hyaluronan or hyaluronic acid (see, e.g., WO 97/38698; Silver stein et al. Am J Otol. 19(2):196-201 (1998)), or fibrin glue or other fibrin-based vehicle (see, e.g., Balough et al. Otolaryngol. Head Neck Surg. 119:427-31 (1998); Park et al. Laryngoscope 107:1378-81 (1997)). Although these methods may ultimately result in delivery of drug into the inner ear (e.g., by perfusion through the round window membrane), delivery of the therapeutic agent is generally not well controlled and/or use of the carrier materials may be associated with adverse side effects. For example, use of gelatin-based materials such as Gelfoam can cause fibrosis in the middle ear cavity (see, e.g., Laurent et al. Am. J. Otolaryngol 7(3):181-6 (1986); Liening et al. Otolaryngol. Head Neck Surg. 116:454-7 (1997)). Furthermore, naturally-occurring carrier materials generally do not retain their shape following introduction into the ear (e.g., the materials are naturally viscous or become more liquid upon introduction into the ear). The changes in the shape of the carrier materials make it extremely difficult to completely retrieve the materials from the site of introduction if such should be desired (e.g., to terminate therapy). Changes in the shape of the carrier material may even prevent delivery of additional therapeutic agents in subsequent treatments (see, e.g., Silverstein et al. Am J. Otol 18:586-9 (1997), describing how gelfoam becomes paste-like and prevents future injections of this material from reaching the inner ear fluids).
Of further interest regarding the delivery of therapeutic agents to the middle ear, inner ear, and middle-inner ear interface tissue structures described in U.S. Pat. Nos. 5,421,818; 5,474,529; and 5,476,446, each of which are incorporated herein by reference. U.S. Pat. No. 5,421,818 describes a treatment system which comprises a reservoir portion with an internal cavity designed to retain a supply of therapeutic fluid compositions therein. The device further comprises fluid transfer means (e.g. pores, a semi-permeable membrane, and the like) which allows fluid materials to be delivered on-demand to, for example, the round window membrane for subsequent diffusion into the inner ear. U.S. Pat. No. 5,474,529 involves a therapeutic treatment apparatus with a plurality of reservoir portions and multiple stem portions designed for implantation into, for example, the endolymphatic sac and duct using standard microsurgical techniques. Finally, U.S. Pat. No. 5,476,446 discloses a therapeutic treatment apparatus comprising a reservoir portion for retaining liquid medicine materials therein, and first and second stems. The second stem can reside within the patient""s external auditory canal lateral to the ear drum, with the first stem residing within, for example, an opening formed in the stapes footplate/annular ligament so that medicine materials can be delivered to the inner ear from the reservoir portion.
A different approach for transferring materials into and out of the inner ear (e.g., via the round window niche/round window membrane) is disclosed in co-owned pending U.S. patent application Ser. No. 08/874,208 (Arenberg et al.) entitled xe2x80x9cINNER EAR FLUID TRANSFER AND DIAGNOSTIC SYSTEMxe2x80x9d and filed on Jun. 13, 1997, which application is incorporated herein by reference. This application describes a system in which one or more fluid transfer conduits are provided which are operatively connected to a cover member that can be placed over or at least partially within the niche to create a fluid-receiving zone. The cover member can be a plate-like structure or can comprise a compressible material. Representative compressible compositions for use with the cover member include substantially non-fluid absorbent, foam-type products such as polyethylene foam, polyether foam, polyester foam, polyvinyl chloride foam, polyurethane foam, and sponge rubber (e.g. synthetic or natural).
A still further system for transferring materials into and out of the inner ear is disclosed in co-owned pending U.S. patent application Ser. No. 09/121,460 (Arenberg et al.) entitled xe2x80x9cFLUID TRANSFER AND DIAGNOSTIC SYSTEM FOR TREATING THE INNER EARxe2x80x9d and filed on Jul. 23, 1998, which application is also incorporated herein by reference. This particular system employs a fluid transfer conduit comprising one or more passageways therethrough. Attached to the conduit is an inflatable bladder sized for insertion at least partially within an internal cavity of the ear (e.g., the round window niche). When inflated, the bladder engages the internal side wall 0f the internal cavity, thereby securing the bladder and part of the conduit within the internal cavity, thus allowing transfer of fluids to and from the internal cavity.
Notwithstanding the approaches described above which provide a number of benefits, there remains a need in the field for additional methods and devices for delivery of therapeutic agents to the inner ear. The present invention provides such methods and devices.
The present invention provides methods and devices for controlled delivery of a therapeutic agent to an internal cavity of the ear, particularly to the inner ear. In general, the invention uses a drug delivery unit for inner ear treatment which employs a portion of carrier media material containing one or more therapeutic agents therein. The carrier media material is designed to release the therapeutic agents in a controlled manner over time. The drug delivery unit is shaped and sized for placement of at least a portion thereof in the round window niche of a patient. The released therapeutic agents come in contact with the round window membrane and pass therethrough into the inner ear for treatment purposes. This system provides many benefits ranging from the ability to deliver drugs in a site specific, controlled manner to the transfer of such materials with minimal patient discomfort and monitoring requirements.
It is an object of the present invention to provide a custom-designed system for delivering therapeutic agents to inner ear tissues and tissue regions in a highly effective manner.
It is another object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which is accomplished with a minimal degree of surgical intervention.
It is another object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which is capable of both sustained and controlled (e.g. time-release) drug transfer in an accurate and selective manner.
It is another object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which is capable of being used effectively in patients of all ages and is likewise able to deliver a wide variety of therapeutic agents in differing dosages. These dosages include microdosing situations where drugs are to be supplied in nanogram or microgram quantities.
It is a still further object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which is accomplished with a minimal degree of patient discomfort.
It is a still further object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions that is safe, effective, and requires little if any physician monitoring.
It is an even further object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which involves a minimal level of expense and can be used to treat a wide variety of inner ear conditions.
It is an even further object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions which provides the treating physician with a considerable degree of control over the duration of drug delivery, the rate of drug transfer into the inner ear, and the types of drugs which may be administered.
It is an even further object of the invention to provide a system for delivering therapeutic agents to inner ear tissues and tissue regions using a controlled release carrier media material which is combined (e.g. impregnated, filled, or coated) with one or more therapeutic agents. At least a portion of the carrier media material (e.g., in the form of a discrete unit or xe2x80x9cmassxe2x80x9d) is then inserted at least partially into, for example, the round window niche of a patient adjacent or against the round window membrane. The natural physiological environment of the round window niche (including the pH, temperature level, and moisture level thereof) cooperates with the carrier media material to cause the drug materials to be released therefrom. Where the carrier media material comprises a biodegradable material, the biodegradable material portion is absorbed into adjacent tissue regions and thereafter metabolized by the body. Where the carrier media material comprises a non-biodegradable material which, for example, does not degrade over time in the body, such type of material is generally retained within the site of implantation throughout the course of therapy and can be later removed. In one embodiment, the carrier media material retains its shape (e.g., by virtue of cross linking) so that the drug delivery unit can be physically removed from the round window niche or other implantation site after drug delivery or when it is desirable to terminate therapy.
After release into the round window niche as discussed above, therapeutic agent passes into and through the round window membrane. This step is accomplished in accordance with a variety of physical interactions between the therapeutic agent and the round window membrane including, but not necessarily limited to, the following processes: osmosis, diffusion, electrodifflusion, electroosmosis, active/passive transport, wicking by surface tension or a combination thereof. There are other important details, modifications, and embodiments associated with this unique process which will be discussed further below. As a result, the desired therapeutic agents (e.g. drug compounds) are delivered in a controlled, complete, substantially automatic, and uniform manner with a minimal degree of patient discomfort and physician interaction. In this regard, the present invention represents a substantial advance in the treatment of inner ear tissues and otologic drug delivery.
The present invention thus involves a minimally-invasive drug delivery system and method which offers many advantages including: (1) the repeatable, accurate, efficient, and sustained active/passive delivery of therapeutic agents into the inner ear through the round window membrane (or other middle-inner ear interface structures as discussed further below); (2) the delivery of a wide variety of therapeutic agents (e.g. pharmaceutical preparations) in a safe and direct manner through the use of controlled-release carrier materials; (3) the accomplishment of effective drug delivery without overly invasive surgical procedures; (4) the ability to initiate a single drug delivery step which will result in the controlled/sustained delivery of therapeutic agents into the inner ear of a patient without further medical procedures, monitoring, or patient discomfort; and (5) achievement of the benefits described above through the use of a controlled release carrier media material which is combined with one or more therapeutic agents (e.g. pharmaceutical compositions) and placed at least partially into the round window niche of a patient in the form of a mass consisting of a pellet or other structural unit. Accordingly, the present invention represents an advance in the art of inner ear treatment, diagnosis, and medicine delivery as described in detail below.
As noted above, the present invention involves a highly effective and minimally-invasive method for the controlled and site-specific transfer (e.g. xe2x80x9cmicrodosingxe2x80x9d) of physician-specified therapeutic agents into the inner ear via the round window membrane (which is centrally located within the round window niche as previously discussed). While the invention shall primarily be described herein with reference to the round window membrane/round window niche, it shall also be applicable to other internal cavities within the ear which will become readily apparent from the discussion provided below. Thus, all of the information presented herein regarding the claimed materials, methods, and their relationship to the round window niche shall be incorporated by reference relative to other internal ear cavities (natural or man-made) without limitation.
The following summary of the present invention represents a general overview of the novel features mentioned above. A more detailed disclosure of the invention will be presented later in the Detailed Description of Preferred Embodiments. To accomplish the goals recited herein, a discrete drug delivery unit is first provided. The drug delivery unit (which is sized for partial or complete placement within the round window niche or other internal ear cavity as previously noted) is comprised of two main components, namely, (1) at least one controlled release carrier media material; and (2) one or more selected therapeutic agents combined (preferably, but not exclusively, in a homogeneous manner) with the carrier medial material. The term xe2x80x9ctherapeutic agentsxe2x80x9d shall be construed to encompass drugs and any other materials in liquid, solid, semi-solid, crystalline, or other forms which provide therapeutic benefits in connection with inner ear tissues or the other tissues of interest. Supplemental compositions including but not limited to plasticizers, lubricants, and the like may also be employed within the drug delivery unit in selectively-variable amounts as needed and determined by preliminary pilot testing. In this regard, the present invention shall not be restricted to any particular carrier media materials, therapeutic agents, supplemental compositions, quantities of these ingredients, and other operational parameters unless otherwise specified herein. Representative materials which may be employed in connection with the ingredients used to produce the claimed drug delivery units shall be listed below in the Detailed Description of Preferred Embodiments section.
In one embodiment, the carrier media material comprises at least one material of synthetic origin. This allows for the selection and custom design of a carrier media material that has optimum delivery and/or other desired characteristics, e.g., retention of shape, avoidance or mitigation of adverse side effects (e.g., allergic reactions, irritation, induction of fibrosis, etc.), increased drug loading or optimized drug release characteristics. In this regard, the term xe2x80x9csyntheticxe2x80x9d as used herein shall be defined to encompass compositions of a non-animal origin as discussed further below, with the placement of a synthetic carrier media material directly in the round window niche constituting a novel development with a high safety profile. It should also be noted that the term xe2x80x9canimalxe2x80x9d as used herein shall also encompass humans. Thus, the word xe2x80x9csyntheticxe2x80x9d shall likewise exclude products of human origin.
In another embodiment, the carrier media material comprises polymeric materials that are cross linked to provide a drug delivery unit that substantially retains its shape during release of the therapeutic agent(s). For example, the cross linking of the carrier media material can be such that, upon addition of water at approximately neutral pH and at about body temperature of the subject into which the material is to be implanted, the drug delivery unit swells a substantially predicable amount. In general, the carrier material can be cross linked physically or chemical to swell a predictable amount typically in the range of from about 20% to about 200% of its original dimensions. Normally the cross linked carrier material will swell at least about 25% to 100%, and may swell up to 200% or more of its original dimensions. The actual degree of cross linking will vary according to the actual material(s) cross linked, shape and size of the delivery unit, and other factors that will be readily apparent to the ordinarily skilled artisan. In one embodiment cross linking is accomplished using one or more synthetic cross linking agents or by physical cross linking processes, i.e., by subjecting the material to be cross linked to conditions to which the material is not naturally exposed to provide a material that does not occur in nature in the course of natural processes to which the material is exposed (e.g., gamma irradiation, ultraviolet irradiation, thermal cross linking, pressure, and the like). Cross linking can be accomplished through covalent bonds, ionic bonds, hydrogen bonds, or crystallization domains. Suitable cross linking agents and methods are well known in the art and will vary according to the material used and other factors that will be readily apparent to the ordinarily skilled artisan upon reading the present specification.
The selected drug delivery unit (which may be configured in many different forms without limitation including pellets, disks, spheres, cubes, cylindrical units, strands, amorphous masses, gels, pastes, and the like) is then placed within the round window niche of the subject under consideration. The term xe2x80x9cplacementxe2x80x9d or xe2x80x9cplacedxe2x80x9d as used herein shall involve either partial or complete insertion of the drug delivery unit into the round window niche or other ear cavity of interest (e.g. as much as is needed in accordance with the medical procedure[s] of interest). Since a preferred embodiment of the invention will involve placement of the drug delivery unit in the round window niche, the remainder of this discussion will again focus on this location with the understanding that it is equally applicable to insertion of the drug delivery unit in other ear cavities as previously noted.
As outlined in greater detail below, the round window niche includes an internal side wall therein. Immediately upon placement of the drug delivery unit within the round window niche, the drug delivery unit will come in direct physical contact with an internal side wall of the niche. Likewise, in view of the relatively small size of the niche, insertion of the drug delivery unit therein will typically cause it to be located directly adjacent or xe2x80x9cagainstxe2x80x9d the round window membrane. The term xe2x80x9cagainstxe2x80x9d as used herein indicates that the drug delivery unit is proximal to the round window membrane and is not meant to exclude the separation of the drug delivery unit and the round window membrane by a quantity of therapeutic agent (e.g., a film) or other fluid material. Both xe2x80x9cagainstxe2x80x9d and xe2x80x9cadjacentxe2x80x9d thus can allow for at least a minimal fluid transfer space between the drug delivery unit and the round window membrane.
The claimed method is highly effective regardless of the particular orientation of the drug delivery unit relative to the round window membrane. The drug delivery unit need only be oriented relative to the membrane and positioned within or adjacent the round window niche to as to facilitate contact of a therapeutic agent of the unit with the round window membrane. For example, where the delivery unit is designed to allow flow of therapeutic agent out of the unit, delivery of the agent to the round window membrane does not necessarily require that the delivery unit per se physically contact the round window membrane, but only that therapeutic agent that originates from the delivery unit reach and contact the round window membrane so as to facilitate diffusion of the agent into and through the membrane to reach the desired site of action within the inner ear.
Once the drug delivery unit is positioned (e.g. placed) at least partially within the round window niche as discussed above, therapeutic agent can be released from the carrier media material as a result of, for example, diffusion of the agent from the carrier material (e.g., while the carrier material substantially retains the shape at the time of implantation), solvent drag by wicking of the solvent, dissolution of the carrier material (e.g., biodegradation of the carrier material), or electrodiffusion from the carrier material. As a result, the drug delivery unit allows release of the desired therapeutic agents. The therapeutic agent may diffuse directly into the round window membrane or permeate across a fluid film in contact between the delivery unit and the round window membrane. The term xe2x80x9callowsxe2x80x9d as used in connection with the release of therapeutic agents from the drug delivery unit shalt involve leaving the drug delivery unit in the patient until therapeutic agent release occurs on a partial or complete basis. This may involve a time period ranging from minutes to hours depending on the compositions under consideration. The precise physical mechanism associated with drug release will depend on the particular carrier media material being used as discussed below. Therapeutic agent release is accomplished over time in accordance with the unique physical environment of the round window niche including its pH, temperature, moisture characteristics, the type of carrier medial material being employed, and other comparable factors. If the carrier media material associated with the drug delivery unit is biodegradable, it will ultimately be absorbed into adjacent tissues in the body, followed by metabolic degradation thereof Non-biodegradable materials may be removed by the treating physician after drug delivery using a number of minimally-invasive surgical techniques.
During the foregoing process, the previously-entrained therapeutic agent will be released from the drug delivery unit and will thereafter come in contact with the round window membrane. The therapeutic agent will then pass through the membrane in accordance with a variety of natural physical processes including but not limited to osmosis, diffusion, electrodiffusion, active/passive transport, or a combination thereof. The therapeutic agents can then effectively treat the inner ear tissues of concern.
The time needed to achieve complete release of the therapeutic agent from will vary in view of numerous factors including but not limited to the type of carrier media material being employed, the overall size of the drug delivery unit, the ambient environmental conditions within the round window niche, and other considerations as determined by routine preliminary investigation. Delivery times can range from a few hours to many months which may be adjusted in accordance with the factors listed above. In one embodiment, the drug delivery unit provides for delivery over a period from at least about 36 hours to several weeks or months or more. Where the drug delivery unit is operably connected to a reservoir of therapeutic agent, delivery of the agent can be maintained over an extended course of therapy, e.g., from at least about 48 hours to 12 months, generally from at least about 72 hours to about 6 months or more (e.g., until the reservoir is substantially emptied or, where the reservoir is replaced or refilled, for an even more extended period (e.g., for the lifetime of the subject)). In this regard, the claimed invention shall not be restricted to any drug delivery times or materials associated with the drug delivery unit as previously indicated. Likewise, specific examples of these items will again be presented below in the Detailed Description of Preferred Embodiments section.
The process described herein again offers a number of important benefits. In particular, site-specific transfer of the desired therapeutic agents into the inner ear can occur in a controlled, complete, and uniform manner with minimal patient discomfort. Likewise, as previously discussed, the claimed process is characterized by a high level of versatility in connection with (1) the size of the drug delivery units being employed; (2) the particular therapeutic agents combined with the carrier media material; (3) the specific ingredient proportions within the drug delivery units including the concentrations of therapeutic agents (which can be varied as needed); and (4) the mechanism of dispensing medication. In accordance with these benefits, the present invention represents a significant advance in inner ear therapy which enables treatment to occur in a very efficient, substantially automatic manner with minimal monitoring requirements.
As a further note, drug delivery time may be modified (e.g. increased or decreased) in connection with a given drug delivery unit through the addition of supplemental fluid materials (including but not limited to water, saline solution, additional therapeutic agent, and the like). The need for supplemental fluid addition will be determined in accordance with routine preliminary testing on the patient and drug delivery units under consideration. Furthermore, supplemental fluid transfer to the selected drug delivery unit within the round window niche (or other internal ear cavity) may be accomplished using the particular devices disclosed in co-owned U.S. Pat. Nos. 5,421,818; 5,474,529, and 5,476,446 all to Arenberg et al., as well as co-owned pending U.S. patent application Ser. No. 08/874,208 (filed on Jun. 13, 1997) and Ser. No. 09/121,460 (filed on Jul. 23, 1998) which are also to Arenberg et al. The quantity of supplemental fluid materials to be delivered will depend on many factors as determined by initial patient testing including but not limited to the carrier media material being employed, the desired drug delivery rate, and the like.
In an alternative embodiment to be discussed in further detail below, the drug delivery units of the present invention may be adhered to or formed on the terminal end of an elongate member. The end of the elongate member having the drug delivery unit thereon is then inserted at least partially into the round window niche as discussed above. This technique substantially facilitates insertion and subsequent physical manipulation of the drug delivery unit within the round window niche (e.g., removal when therapy is to be terminated or when delivery of therapeutic agent is complete).
The elongate member may remain attached to the drug delivery unit during release of the therapeutic agent or can be configured to detach from the drug delivery unit after placement thereof in the round window niche. On-demand detachment can be accomplished by selection of the manner in which the drug delivery unit is secured to the elongate member (for example, by choosing the proper adhesive, etc.).
In one embodiment, the elongate member can serve as a conduit for delivery of therapeutic agents for filling or refilling the drug delivery unit and/or for delivery of supplemental fluids to the drug delivery unit as described above. For example, the elongate member can be a hollow member comprising a lumen which can be substantially empty, or completely or partially filled with an absorptive material to facilitate transport of therapeutic agent from one end of the elongate member to the opposite end comprising the drug delivery unit. Alternatively, where the elongate member can br a solid member comprised of a material which allows transport of a therapeutic agent from one end of the elongate member to the opposite end which serves as the drug delivery unit (e.g., by wicking). Where the elongate member is sufficiently long (e.g., of a length sufficient to enable the clinician to manipulate the drug delivery unit within the round window niche from a location outside the ear (or from the middle/external ear as needed), therapeutic agent can be delivered through the second end positioned, for example, on the exterior of the tympanic membrane or within the middle ear. Delivery of the agent or other supplemental fluids to the delivery unit can be further facilitated by the presence of sidewall apertures adjacent or at the portion of the elongate member in contact with the carrier material.
In another embodiment, the elongate member is operatively connected to a reservoir of therapeutic agent to facilitate delivery of supplemental fluids and/or therapeutic agent to the drug delivery unit. The reservoir, which can optionally be refillable, can be a fluid-filled bladder or pouch, or can be a reservoir of a drug delivery device (e.g., a pump), where the drug delivery device facilitates movement of fluid from the reservoir by diffusive or convective mechanism. Where the elongate member is operatively connected to a reservoir, the elongate member can comprise, for example, i) a substantially fluid impermeable or semi-permeable material, ii) a fluid-absorbent material (i.e., a material that absorbs fluid to facilitate movement of fluid from, for example, a reservoir to a desired delivery site (e.g., to the drug delivery unit or direct to the round window niche)), or iii) a combination thereof.
The present invention shall not be restricted to any particular elongate members or size parameters associated with these structures which may be varied as needed. The elongate members may involve solid rod or strip-like units, hollow members of tubular configuration, string-like elements, and the like. A hollow, tubular elongate member is of considerable value in facilitating the flow of supplemental fluid materials to the drug delivery unit as noted above (if such fluid materials are to be employed). The elongate members may be produced from many different materials including but not limited to plastics (e.g. polyethylene or silicone rubber, or polycarbonate materials suitable for medical use).
In a still further embodiment, the drug delivery unit may be formed on the terminal end of an elongate member made of an electrically conductive material (e.g. metal) which is optimally configured in the form of a wire as disclosed in U.S. Pat. Nos. 5,421,818; 5,474,529, and 5,476,446 all to Arenberg et al. The terminal end of this structure (with the drug delivery unit adhered thereto or molded thereon) can then be inserted at least partially into the round window niche, with drug delivery occurring as discussed above.
The elongate member made of conductive material (also characterized herein as an xe2x80x9celongate conductive memberxe2x80x9d) constitutes an electrical potential transmission system which is used to transmit electrical potentials into and out of the inner ear, preferably through the round window membrane. The term xe2x80x9cpotentialxe2x80x9d shall be broadly construed to encompass any type of electrical signal, current, voltage, or impulse regardless of form, magnitude, or origin. In one embodiment discussed in substantial detail below, the elongate conductive member will involve a metallic wire, strip, or other comparable structure with a ball, loop, mushroom, flat, or spoon-shaped tip on the terminal end which preferably protrudes in an outward direction from the drug delivery unit. By placing the tip in direct physical contact with the round window membrane during use of the claimed apparatus (or in contact with tissue materials adjacent thereto which shall be deemed equivalent namely, the mucosa/bone of the round window niche and others), a number of important steps will then take place. These steps include: (1) delivery of the drug to the drug delivery unit, followed by drug transfer into and through the round window membrane; and (2) the transmission of evoked or non-evoked electrical potentials to and/or from the membrane for therapeutic analysis and other purposes using various techniques preferably encompassed within the term xe2x80x9celectrocochleographyxe2x80x9d or xe2x80x9cECoGxe2x80x9d. Iontophoresis procedures may also be facilitated using the components listed above, with this term being defined to involve a process in which electrical energy is employed to transport drug through the round window membrane. Iontophoresis can be used to facilitate transfer of the released drug materials into and through the round window membrane.
As noted above, the selection of any given procedure for placing the drug delivery unit at least partially into the round window niche (or other designated internal ear cavity) will again be determined in accordance with preliminary pilot testing involving the patient under consideration, the conditions being treated, the materials being employed in connection with the drug delivery unit and other related factors. The present invention shall therefore not be restricted to any given approach for placing the drug delivery unit at least partially into the round window niche of a patient.
The present invention represents an advance in the art of inner ear therapy and treatment. The claimed treatment system provides numerous benefits and capabilities as previously noted including but not limited to: (1) the repeatable and sustained delivery of therapeutic agents into the inner ear via the round window membrane (or other middle-inner ear interface tissue structures; (2) the delivery of many different therapeutic agents (e.g. pharmaceutical preparations) to the inner ear in a safe and direct manner; (3) the accomplishment of effective drug delivery without overly invasive surgical procedures; and (4) the use of a single-step method to deliver therapeutic agents into the inner ear of a patient without complex medical procedures, monitoring, and patient discomfort. For these reasons and the other reasons listed below, the claimed invention represents a substantial advance in the art of otological treatment and drug delivery.
These and other objects, features, and advantages of the invention will become readily apparent from the following Brief Description of the Drawings and Detailed Description of Preferred Embodiments.